The Johns Hopkins Lung Cancer SPORE is in its fourteenth year and continues to have as its goals, the performance of highly translational research to provide new means for the prevention of, risk assessment for, early detection of, gauging prognosis of, and therapy for, lung cancers of all types. Our work encompasses collaboration with other Lung Cancer SPORE'S, extensive leveraging of foundation, institutional, and commercial partnering support, and interaction with other NCI initiatives. We use flexibility of the SPORE funding mechanism to extend projects that continually evolve higher and higher translational potential and curtail those that do not. We emphasize incorporation of new concepts and directions to facilitate development of areas that are headed for ultimate translational verification and even movement to common clinical practice. Two projects, Projects 1 and 2, the latter a collaborative venture with the Colorado SPORE, stress biomarker research at the highest translational level. Both involve highest translational level validation of gene DNA hypermethylation markers with high promise for: a) in assays of tumor and lymph node DNA, restaging stage 1 to stage 3 lung cancer and predicting patients with highest risk for rapid disease recurrence;and b) in assays of sputum DNA, predicting individuals at highest risk for imminent development of lung cancer and /or facilitating early diagnosis of the disease. In both projects, implications of the markers for developing epigenetic approaches to adjuvant therapy and prevention will be directly explored. This work also links participation of the Hopkins SPORE with the consortium lloprost chemoprevention trials (Lung Cancer Biomarker Chemoprevention Consortium-LCBCC) involving other Lung Cancer SPORES and, especially, the Colorado SPORE. In terms of developing novel lung cancer therapies, Project 4 is at a very high translational level with correlative science to be conducted in the setting of first in human clinical trials for the inhibition of the enzyme, fatty acid synthase. Project 3, will explore the correlation, in non-small cell lung cancer, of newly found frequent mutations in the NRF2 stress response pathway, that renders this protein constitutively active in the nucleus, with the presence of drug resistance to commonly employed treatment regimens and the possibilities for inhibiting this pathway to reverse chemoresistance. Relevance to public health: The work in this SPORE is directly aimed at refining the detection and management of the leading cause of cancer death, lung cancer.